The objective of this program project is to study the role of different macromolecular components of extracellar matrix in differentiation and expression of malignancy. Matrix components such as fibronectin and different genetic types of collagen as well as laminin and proteoglycans to be isolated will be used to study the molecular interactions leading to formation of extracellar matrix in normal cells and the disturbance of this process in malignant cells. Fragments of fibronectin that interact with collagen, glycosaminoglycans or cell surfaces as well as monoclonal antibodies to them will be prepared and characterized. They will be utilized to study the molecular interactions that regulate the formation of a fibronectin-containing extracellular matrix. This may lead to understanding of the nature of the defect that causes lack of fibronectin matrix in most malignant cells. The expression and distribution of the matrix components in relation to the mesenchymal-epithelial interactions that take place during differentiation of cultured teratocarcinoma cells, early mouse embryos and organoid cultures of fetal tissues will be studies. Antibodies will be used to visualize the matrix proteins. The capacity of such antibodies to perturb differentiation when added to teratocarcinoma cultures will also be studies. The mRNA for the main basement membrane component of differentiating teratocarcinoma cells, laminim, will be isolated, and a cDNA probe will be prepared. This will be used to study the appearance of laminim expression in the differentiation of embryonal carcinoma cells to endodermal cells. Defined matrices will constructed from isolated matrix proteins and examined in electron microscopy. The influence of such matrices on the differentiation of normal and malignant cells as detected by measurement of specific markers will be studied. These studies will contribute to our understanding of the role that cell surface interactions play in directing differentiation and modifying the expression of the malignant phenotype.